Evidence from randomized controlled trials (RCTs) for the causal role of vitamin D on noncommunicable disease outcomes is inconclusive.
The aim of this study was to investigate whether there are ...beneficial or harmful effects of cholecalciferol (vitamin D3) supplementation according to subgroups of remeasured serum 25-hydroxyvitamin D 25(OH)D on cardiovascular and glucometabolic surrogate markers with the use of individual participant data (IPD) meta-analysis of RCTs.
Twelve RCTs (16 wk to 1 y of follow-up) were included. For standardization, 25(OH)D concentrations for all participants (n = 2994) at baseline and postintervention were re-measured in bio-banked serum samples with the use of a certified liquid chromatography–tandem mass spectrometry method traceable to a reference measurement procedure. IPD meta-analyses were performed according to subgroups of remeasured 25(OH)D. Main outcomes were blood pressure and glycated hemoglobin (HbA1c). Secondary outcomes were LDL, HDL, and total cholesterol and triglycerides; parathyroid hormone (PTH); fasting glucose, insulin, and C-peptide; and 2-h glucose. In secondary analyses, other potential effect modifiers were studied.
Remeasurement of 25(OH)D resulted in a lower mean 25(OH)D concentration in 10 of 12 RCTs. Vitamin D supplementation had no effect on the main outcomes of blood pressure and HbA1c. Supplementation resulted in 10–20% lower PTH concentrations, irrespective of the 25(OH)D subgroups. The subgroup analyses according to achieved 25(OH)D concentrations showed a significant decrease in LDL-cholesterol concentrations after vitamin D supplementation in 25(OH)D subgroups with <75, <100, and <125 nmol of −0.10 mmol/L (95% CI: −0.20, −0.00 mmol/L), −0.10 mmol/L (95% CI: −0.18, −0.02 mmol/L), and −0.07 mmol/L (95% CI: −0.14, −0.00 mmol/L), respectively. Patient features that modified the treatment effect could not be identified.
For the main outcomes of blood pressure and HbA1c, the data support no benefit for vitamin D supplementation. For the secondary outcomes, in addition to its effect on PTH, we observed indications for a beneficial effect of vitamin D supplementation only on LDL cholesterol, which warrants further investigation. This trial was registered at www.clinicaltrials.gov as NCT02551835.
OBJECTIVE:We investigated the effects of 2-year folic acid and vitamin B12 supplementation on cognitive performance in elderly people with elevated homocysteine (Hcy) levels.
METHODS:This ...multicenter, double-blind, randomized, placebo-controlled trial included 2,919 elderly participants (65 years and older) with Hcy levels between 12 and 50 µmol/L. Participants received daily either a tablet with 400 µg folic acid and 500 µg vitamin B12 (B-vitamin group) or a placebo tablet. Both tablets contained 15 µg vitamin D3. Data were available for global cognitive functioning assessed by Mini-Mental State Examination (n = 2,556), episodic memory (n = 2,467), attention and working memory (n = 759), information processing speed (n = 731), and executive function (n = 721).
RESULTS:Mean age was 74.1 (SD 6.5) years. Hcy concentrations decreased 5.0 (95% confidence interval −5.3 to −4.7) µmol/L in the B-vitamin group and 1.3 (−1.6 to −0.9) µmol/L in the placebo group. Cognitive domain scores did not differ over time between the 2 groups, as determined by analysis of covariance. Mini-Mental State Examination score decreased with 0.1 (−0.2 to 0.0) in the B-vitamin group and 0.3 (−0.4 to −0.2) in the placebo group (p = 0.05), as determined by an independent t test.
CONCLUSIONS:Two-year folic acid and vitamin B12 supplementation did not beneficially affect performance on 4 cognitive domains in elderly people with elevated Hcy levels. It may slightly slow the rate of decline of global cognition, but the reported small difference may be attributable to chance.
CLASSIFICATION OF EVIDENCE:This study provides Class I evidence that 2-year supplementation with folic acid and vitamin B12 in hyperhomocysteinemic elderly people does not affect cognitive performance.
•45% of this Dutch older population had serum 25(OH)D concentrations <50nmol/L.•Only 6% of the participants with a vitamin D deficiency used vitamin D supplements.•Sun habits are still an important ...determinant of 25(OH)D status in older adults.•35% of the variation in serum 25(OH)D was explained by the determinants under study.
The prevalence of vitamin D deficiency among seniors is high. Whereas sun exposure, vitamin D intake, genes, demographics, and lifestyle have been identified as being important determinants of vitamin D status, the impact of these factors is expected to differ across populations. To improve current prevention and treatment strategies, this study aimed to explore the main determinants of vitamin D status and its relative importance in a population of community-dwelling Dutch older adults.
Serum 25-hydroxyvitamin D (25(OH)D) was measured in 2857 adults aged ≥65 years. Sun exposure was assessed with a structured questionnaire (n=1012), vitamin D intake using a Food Frequency Questionnaire (n=596), and data on genetic variation that may affect 25(OH)D status was obtained for 4 genes, DHCR7 (rs12785878), CYP2R1 (rs10741657), GC (rs2282679), and CYP24A1 (rs6013897) (n=2530).
Serum 25(OH)D concentrations <50nmol/L were observed in 45% of the population; only 6% of these participants used vitamin D supplements. Sun exposure (being outside daily during summer: 66±25nmol/L vs not being outside daily during summer: 58±27nmol/L, P=0.02) and vitamin D intake (per unit μg/day during winter/spring: 3.1±0.75nmol/L, P<0.0001) were associated with higher 25(OH)D concentrations. Major allele carriers of SNPs related to DHCR7, CYP24A1, and GC, as well as CYP2R1 minor allele carriers had the highest 25(OH)D concentrations. Together, sun (R2=0.29), vitamin D intake (R2=0.24), and genes (R2=0.28) explained 35% (R2=0.35) of the variation in 25(OH)D concentrations during summer/autumn period, when adjusted for age, sex, BMI, education, alcohol consumption, smoking, physical activity, and self-rated health status (n=185).
The investigated determinants explained 35% of 25(OH)D status. Of the three main determinants under study, sun exposure still appeared to be an important determinant of serum 25(OH)D in older individuals, closely followed by genes, and vitamin D intake. Given the low frequency of vitamin D supplement use in this population, promoting supplement use may be an inexpensive, easy, and effective strategy to fight vitamin D deficiency.
Background: Elevated plasma homocysteine concentrations are a risk factor for osteoporotic fractures. Lowering homocysteine with combined vitamin B-12 and folic acid supplementation may reduce ...fracture risk.Objective: This study B-vitamins for the PRevention Of Osteoporotic Fractures (B-PROOF) aimed to determine whether vitamin B-12 and folic acid supplementation reduces osteoporotic fracture incidence in hyperhomocysteinemic elderly individuals.Design: This was a double-blind, randomized, placebo-controlled trial in 2919 participants aged ≥65 y with elevated homocysteine concentrations (12–50 μmol/L). Participants were assigned to receive daily 500 μg vitamin B-12 plus 400 μg folic acid or placebo supplementation for 2 y. Both intervention and placebo tablets also contained 600 IU vitamin D3. The primary endpoint was time to first osteoporotic fracture. Exploratory prespecified subgroup analyses were performed in men and women and in individuals younger than and older than age 80 y. Data were analyzed according to intention-to-treat and per-protocol principles.Results: Osteoporotic fractures occurred in 61 persons (4.2%) in the intervention group and 75 persons (5.1%) in the placebo group. Osteoporotic fracture risk was not significantly different between groups in the intention-to-treat analyses (HR: 0.84; 95% CI: 0.58, 1.21) or per-protocol analyses (HR: 0.81; 95% CI: 0.54, 1.21). For persons aged >80 y, in per-protocol analyses, osteoporotic fracture risk was lower in the intervention group than in the placebo group (HR: 0.27; 95% CI: 0.10, 0.74). The total number of adverse events (including mortality) did not differ between groups. However, 63 and 42 participants in the intervention and placebo groups, respectively, reported incident cancer (HR: 1.56; 95% CI: 1.04, 2.31).Conclusions: These data show that combined vitamin B-12 and folic acid supplementation had no effect on osteoporotic fracture incidence in this elderly population. Exploratory subgroup analyses suggest a beneficial effect on osteoporotic fracture prevention in compliant persons aged >80 y. However, treatment was also associated with increased incidence of cancer, although the study was not designed for assessing cancer outcomes. Therefore, vitamin B-12 plus folic acid supplementation cannot be recommended at present for fracture prevention in elderly people. The B-PROOF study was registered with the Netherlands Trial Register (trialregister.nl) as NTR1333 and at clinicaltrials.gov as NCT00696414.
To develop and validate a prognostic model to predict deterioration in health-related quality of life (dHRQoL) in older general practice patients with at least one chronic condition and one chronic ...prescription.
We used individual participant data from five cluster-randomized trials conducted in the Netherlands and Germany to predict dHRQoL, defined as a decrease in EQ-5D-3 L index score of ≥5% after 6-month follow-up in logistic regression models with stratified intercepts to account for between-study heterogeneity. The model was validated internally and by using internal–external cross-validation (IECV).
In 3,582 patients with complete data, of whom 1,046 (29.2%) showed deterioration in HRQoL, and 12/87 variables were selected that were related to single (chronic) conditions, inappropriate medication, medication underuse, functional status, well-being, and HRQoL. Bootstrap internal validation showed a C-statistic of 0.71 (0.69 to 0.72) and a calibration slope of 0.88 (0.78 to 0.98). In the IECV loop, the model provided a pooled C-statistic of 0.68 (0.65 to 0.70) and calibration-in-the-large of 0 (−0.13 to 0.13). HRQoL/functionality had the strongest prognostic value.
The model performed well in terms of discrimination, calibration, and generalizability and might help clinicians identify older patients at high risk of dHRQoL.
PROSPERO ID: CRD42018088129.
•Multimorbidity and polypharmacy increase the risk of deterioration in quality of life.•First IPD-based quality of life prognostic model for older multimorbid patients.•Model performed well in terms of discrimination, calibration, and generalizability.•Baseline quality of life and functional status have the strongest prognostic power.•Quality of life/functionality appraisal might help identify high-risk patients.
When using incomplete or non-representative real-world data (RWD), bias is more likely to occur. The aim of the current study was to assess the completeness and representativeness of the PHARMO GP ...data for the Dutch population.
A cross-sectional study was performed. The PHARMO GP data comprise data from electronic health records registered by GPs. Data on the Dutch population were obtained from Statistics Netherlands (CBS), which offers publicly available data on several themes. The standardized difference (std.diff) was used to compare proportions between the PHARMO GP population and the Dutch population. An absolute std.diff >0.2 was considered a difference.
On January 1st, 2018, 3,466,321 persons were included in the PHARMO GP data (mean age: 41.6 years, 49.7% males). The sex and age distribution was similar to the Dutch population. The PHARMO GP data captured less not urbanized areas compared to the Dutch population (not urbanized areas: 9.4% vs 17.1% std.diff: -0.23). Regarding medication use, only the pharmacological subgroups "viral vaccines" and "hormonal contraceptives for systemic use" differed (std.diff >0.2); use in the GP data was more complete than in the Statistics Netherlands (CBS) data. No differences were observed regarding diagnoses.
The PHARMO GP data are representative of the Dutch population with regard to the demographic characteristics and diagnoses in primary care. Medication data in the PHARMO GP data are more complete than national statistics, and differences are related to reimbursement. Use of the data and interpretation of results based on these sources should be done with experts on the data sources, the Dutch healthcare system and (pharmaco)epidemiology.
GPs have been shown to be important providers of medical care during pregnancy, however, little evidence exists on their awareness of pregnancy when prescribing medication to women.
To assess GPs' ...awareness of pregnancy and its association with prescribing medication with potential safety risks.
Population-based study using confirmed pregnancy records linked to GP records from the PHARMO Perinatal Research Network.
GPs' awareness of pregnancy, defined as the presence of a pregnancy confirmation in the GP information system during pregnancy, was assessed from 2004 to 2020. GP prescriptions of medication with potential safety risks were selected during pregnancy and its association with GPs' awareness of pregnancy was assessed using multivariable logistic regression.
A pregnancy confirmation was present in the GP records for 48% (
= 67 496/140 976) of selected pregnancies, increasing from 28% (
= 34/121) in 2004 to 63% in 2020 (
= 5763/9124). During 3% (
= 4489/140 976) of all pregnancies, the GP prescribed highly hazardous medication with teratogenic effects that should have been (temporarily) avoided. Pregnancy was GP confirmed for only 13% (
= 585/4489) at the first occurrence of such a prescription. Comparative analyses showed that women without a pregnancy confirmation were 59% more likely to be prescribed this highly hazardous medication (odds ratio OR 1.59, 95% confidence interval CI = 1.49 to 1.70) compared with those with a confirmed pregnancy.
Results of this study indicate a potential issue with GP awareness about pregnancy status at the time medication with potential safety risks is prescribed. Although pregnancy registration by GPs improved over the years, inadequate use still seems to be made of the available information systems for appropriate drug surveillance.
Elevated homocysteine concentrations are associated with a decline in physical function in elderly persons. Homocysteine-lowering therapy may slow down this decline. This study aimed to examine the ...effect of a 2-year intervention of vitamin B12 and folic acid supplementation on physical performance, handgrip strength, and risk of falling in elderly subjects in a double-blind, randomized placebo-controlled trial. Participants aged ≥65 years with elevated plasma homocysteine concentrations 12–50 µmol/L (
n
= 2919) were randomly assigned to daily supplementation of 500 µg vitamin B12, 400 µg folic acid, and 600 IU vitamin D3, or to placebo with 600 IU vitamin D3. Physical performance (range 0–12) and handgrip strength (kg) were measured at baseline and after 2 years. Falls were reported prospectively on a research calendar. Intention-to-treat (primary) and per-protocol (secondary) analyses were performed. Physical performance level and handgrip strength significantly decreased during the follow-up period, but this decline did not differ between groups. Moreover, time to first fall was not significantly different (HR: 1.0, 95 % CI 0.9–1.2). Secondary analyses on a per-protocol base identified an interaction effect with age on physical performance. In addition, the treatment was associated with higher follow-up scores on the walking test (cumulative OR: 1.3, 95 % CI 1.1–1.5). Two-year supplementation of vitamin B12 and folic acid was neither effective in reducing the age-related decline in physical performance and handgrip strength, nor in the prevention of falling in elderly persons. Despite the overall null-effect, the results provide indications for a positive effect of the intervention on gait, as well as on physical performance among compliant persons >80 years. These effects should be further tested in future studies.
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